Maintenance of body homeostasis is critical to survival; animals must detect and correct chemical and thermal imbalances as well as eliminate toxic compounds. Internal sensory neurons innervate various internal organs and provide information about internal physiological state to the nervous system. Internal sensory neurons are conserved across species and yet are poorly understood compared to external sensory neurons. In particular, there is a large gap in knowledge of the internal sensory neural circuitry and the underlying molecular mechanisms for detecting internal state. These gaps in our knowledge may be due to the relative complexity and genetic inaccessibility of specific subpopulations of neurons in these circuits. To overcome these challenges, we propose to combine powerful anatomic, genetic, and functional methods and provide an entry point into studying internal sensory circuits in the Drosophila nervous system. In this proposal we will build on state-of-the-art serial electron microscopy that has identified synaptic connectivity of internal sensory neuron circuits and further propose to (a) use genetically-encoded indicators of neural activity to assess activity in deep, hard-to-access internal sensory neuron populations, and (b) use powerful Drosophila genetic tools to elucidate the molecular mechanisms that mediate sensory transduction of internal sensory neurons, as well as to manipulate activity of specific subcomponents of the neural circuit to elucidate their role in maintaining physiological homeostasis.